Bone disease, a serious complication of primary biliary cirrhosis (PBC), causes disabling bone pain and pathological fractures in at least 20% of patients. Its etiology is unknown. In patients from the United States, alterations of calcium homeostasis and vitamin D metabolism do not play a major role and histological evidence of osteomalacia is rare. Our prelminary studies show that 38% of premenopausal patients with PBC have vertebral density values below the fracture threshold and, in contrast with reports in the literature, that the primary abnormality is osteoporosis associated with a decrease in bone formation. We propose a systematic study of the metabolic bone disorder associated with PBC. Specifically, our aims are 1) to define and characterize the abnormalities of bone turnover and mineral metabolism in pre-menopausal PBC patients, and 2) to assess the therapeutic efficacy and safety of sodium fluoride and calcium in treatment. Sixty premenopausal PBC patients will be studied prospectively. All will have baseline studies of bone turnover consisting of iliac crest bone biopsy, assessment of bone density of the lumbar spine (by dual photon absorptiometry, a newly developed method with precision error of only 2.3%); measurement of serum bone G1a-protein (a specific and sensitive new marker for bone formation); radiocalcium absorption, and other metabolic and hormonal studies. Twelve of these patients (selected so that they are characteristic of the larger group) will have more intensive studies including calcium balance, radiocalcium kinetic studies and measurement of serum vitamin D metabolites (25-OH-D, 24, 25(OH)2D3, 1,25(OH)2D) and sequence-specific radioimmunoassays for parathyroid hormone. Patients will then be randomized, stratified and enrolled in a four year prospective, double-blind clinical trial with two treatment arms: 1) sodium fluoride and calcium 2) placebo and calcium. Patients will be seen yearly for examination, bone density, and biochemical studies. Complete baseline studies will be repeated at the end of the four years of treatment. The main response parameters will be changes in spinal density, changes in biochemical markers of bone metabolism and changes in bone remodeling and in trabecular bone mass as assessed by iliac crest bone biopsy. Our long range goals are to establish effective therapy in PBC-related bone disease and, through characterization of the disorder, apply the findings to other metabolic bone diseases.